Research Article

iMedPub Journals 2018

Chemical informatics
www.imedpub.com ISSN 2470-6973 Vol. 4 No. 1:1

DOI: 10.21767/2470-6973.100026

Every Jack has His Jill: Finding a Target for
Your Combinatorial Library
Abstract
Pharmaceutical companies regularly run campaigns to evolve their proprietary
chemical libraries which are among their most valuable assets. Ultimate goal with
those library expansions is to address novel chemical space with maximal fit to
pharmaceutically relevant targets which is beyond just applying property or drug-
likeness filters. In this work we present a structured and highly automated process
to identify putative biological targets starting from any chemistry-driven virtual
or existing compound library. Multiple ligand similarity searches are performed
in ChEMBL ligand space, linking library compounds to targets from ChEMBL
database. The results are presented to the computational chemist in a highly
intuitive and interactive manner. For a set of targets selected by a scientist, holo
crystal structures are automatically retrieved and prepared for docking. The co-
crystallized ligand, ChEMBL compounds and combinatorial library are then docked
by an automatic procedure. The scientist finally is provided with a holistic picture of
library-target fit hypotheses to draw his conclusions about relevant targets, library
adjustments, library re-designs and ideas for completely new virtual libraries.
Keywords: Library design; Target fishing; Automated workflow
Received: December 21, 2017; Accepted: December 26, 2017; Published: January 01,
2018
Introduction
The chemical library belongs to the biggest research assets
of any pharmaceutical company. Such screening libraries are
typically between one to five million compounds [1]. Whether
the full library or only subsets are tested in HTS campaigns and
how such subsets are composed depends on target areas, assay
designs and company’s strategy. HTS and especially in vitro and
in vitro assays of individual compounds are costly in terms of
substance consumption. Therefore, all libraries bleed out. Instead
of resynthesizing old compounds, companies set up campaigns
to evolve the libraries into new chemical space following one of
three strategies, namely, buying from chemical catalogs, buying
readily available proprietary compounds or designing novel
proprietary chemistry. Typical design concept for novel libraries
is to create structurally diverse compounds with Lipinski drug-like
[2] or lead-like [3,4] properties.
Since chemical space is almost infinite with approximately 1060
compounds with a molecular weight lower than 500 Da, [5] and
currently only about 10 to 20 million compounds relevant to drug
discovery are covered by commercial sources and proprietary
repositories, the question arises: which of numerous imaginary
libraries are relevant and which not?
Inna Slynko1,2, Jan KF
Dreher1 and Andreas H
Göller1*
1 Bayer Pharma AG, Medicinal Chemistry
- Computational Chemistry, Wuppertal,
Germany
2 Grünenthal GmbH, Computational
Chemistry, Aachen, Germany
*Corresponding author:
Andreas H Göller
 andreas.goeller@bayer.com
Tel: +49202365442
Bayer Pharma AG, Medicinal Chemistry
- Computational Chemistry, Wuppertal,
Germany.
Citation: Slynko I, Dreher JKF, Göller AH (2018)
Every Jack has His Jill: Finding a Target for Your
Combinatorial Library. Chem Inform Vol. 4 No.
1:1.
One way to address the question of target relevance is to start
from known chemical matter and to apply core modifications like
changes of ring size or type, or shifting nitrogen and functional
groups. Alternatively, one can design libraries purely chemistry-
driven, based on attractive chemical scaffolds, synthesis routes
or concepts like escaping from flatland, [6] giving diversity and
serendipity a chance. Combined with IP space analysis both
routes can yield viable libraries.
We were now interested if it would be possible to find the
right target or target family for a subset of our internal library
designs, which were originally driven by feasible chemistry and
attractive novelty. Or otherwise, if it would be possible to derive a
rationale how to modify such a library design in order to tailor the
respective library to a specific target or target family. We expect
that a library designed with a target family in mind possesses a
higher chance to hit the relevant chemical space, especially, since
there are many indications for existence of privileged scaffolds [7].

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We know also that computational methods, especially high
throughput methods like structure- or ligand-based virtual
screening or target-family likeness filters, are far from perfect
and will at maximum provide certain enrichments. Therefore, we
decided to combine computational methods, which provide us
with a high degree of automation and throughput, with optimum
use of expert knowledge and guidance. Nevertheless, we have
to stress that starting libraries, as well as libraries designed with
help of the process described in this article, have to be strictly
novel, which requires intervention of an expert and cannot be
automated.
Hence the question arises: how to find the matching target for the
library, or at least for some library compounds. In the last years
many researchers looked into this topic mostly from a different
perspective, namely, how to control target selectivity of a lead
compound and avoid adverse effects, [8-10] how to identify
hidden opportunities in drug repurposing projects, [11-13] or
how to support the difficult but promising design of multitarget
drugs [14-16]. Despite other rationale for target fishing presented
here, additional information on potential off-target activity or
selectivity of compounds from a starting library is a welcome
side-product.
Computational target prediction methods published to date
[13,17] can be classified as ligand-based, network-based, side-
effect-based, or protein-structure-based depending on the data
used [18]. Ligand-based methods connect similarity measures
with binding profiles for similar compounds in order to predict
potential targets. Network-based methods incorporate the
knowledge about ligand and target interactions, which are then
represented as networks. Side-effect-based approaches utilize
the information about off-target activities of similar drugs.
Potential targets can also be predicted by protein structure-based
methods including docking, protein-ligand interactions or protein
binding site comparisons, but this is a tedious manual procedure
solely based on profound expert knowledge.
Quite new is the inverse approach-to create ligand bioactivity
fingerprints encoding the hit status of compounds from HTS
campaigns [19,20]. In combination with conventional ligand
fingerprints those allow to identify chemically similar ligands that
should have similar bioactivity profiles.
Ligand-based methods are fast and easy to use, but they are
limited to search spaces of highly similar compounds. To a certain
extent, they are able to extrapolate into new chemical space via
scaffold hopping.
Docking, on the other hand, is dependent on the availability of
protein crystal structures. For about half of the targets relevant to
pharmaceutical research there are no crystal structures available.
Docking, in principle, can identify new chemical matter, but it is
challenging with respect to protein pre-processing and ligand
ranking [18].
Pharmacophore methods, finally, are somewhere in between.
To some extent they can extrapolate by scaffold or substituent
hopping. On the other hand, pharmacophore methods often
provide the user with an overwhelming manifold of hypotheses
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ISSN 2470-6973 Vol. 4 No. 1:1
that without detailed SAR knowledge cannot be separated into
meaningful and chance models.
Weighting the pros and cons of the former concepts we decided
for a hybrid approach. We filter down the published - highly
incomplete and sparsely populated - pharmacological universe
by fast ligand-based methods to a manageable subset. We then
process a user-selected subset of the ligand hit sets related to
specific targets by docking. Our approach is as far as possible
automated for efficient identification of potential biological
targets with co-crystal structures. The general process starts
with multiple automated ligand-based similarity searches in
the ChEMBL [21] database, which contains chemical structures
of small molecules with their associated biological test results
and targets. Consequently, grouping of hits based on biological
target, extraction of structures from Protein Data Bank [22] via
the accession codes and automated docking simulations are
performed.
The approach is novel in the way how multiple computational
methods are combined in an efficient process, providing the
computational chemist with a holistic picture of potential hits
based on the available knowledge. It is implemented in a way to
automate the tedious manual work, to provide an expert with the
capability to interact with results and to allow him to concentrate
on decision-making.
Despite a high degree of automation of this process, the crucial
step will always be the final one, where the real value is generated
by the modeling expert, who will make decisions based on visual
inspection and his experience in order to adjust the combinatorial
library to selected target(s) by adding, replacing or removing
chemical substituents, or exchanging a scaffold. As a result, one
or more novel targeted libraries can be designed.
By our approach we will lose all those targets our library would
show some activity on but where the published ligands are
too dissimilar in 2D metrics. A part of those targets could be
“rescued” by direct docking into the complete crystallized target
space, but even then we would still miss some targets due to the
shortcomings of rigid receptor docking.
We do not aim for the identification of a complete targetome for
our library, but for the identification of targets that fit into the
pathways of our medical indications. We will therefore not aim
for the highest-ranked target, but for the one best fitting to our
project portfolio.
It is also important to understand that we do not describe a
process of automated ligand- and target-based virtual screening.
Instead, the similarity searches are applied as a coarse filter to
identify targets from which the expert selects targets of interest.
Docking is applied to confirm target fit based on pose consistency
between cocrystallized ligand, ChEMBL hits and docked library
compounds and has to be seen as a sharper filter to finally
identify the most appropriate target for our library. In this paper
we present a concept and a first implementation of the process
that can be easily adjusted to individual needs, like adding a
corporate database of chemical structures and biological data,
extending the range of similarity search methods, exchanging
protein preparation and docking method or adding automated

pharmacophore modeling. Though implemented in a commercial
software solution, the described protocol can be also realized
using other tools and software.
Methods and Process Description
The basic concept of our target-fishing approach relies on the
“similarity principle”, [23] according to which similar molecules
exert similar biological activities. Therefore, a combinatorial
library in its whole, its subsets or individual compounds, that are
similar to known actives, should be able to point at targets of
interest. Promising targets, which were identified indirectly using
ligand similarity, are then selected for further investigation via
automated docking. Conceptually, this resembles the process of
experimental target validation using chemical probes.
The automated protocol constructed and executed using the
workflow software Pipeline Pilot [24] can be summarized into
four steps, namely, database preparation, similarity search,
analysis and docking, as it is shown schematically in Figure 1. In a
fifth step, the computational chemists will visually inspect results
and draw informed decisions.
Figure 1 Schematic visualization of the five workflow steps
starting from database preparation and ending with
docking results and visual interpretation. Here PP is
Pipeline Pilot and SQL - Structured Query Language.
© Under License of Creative Commons Attribution 3.0 License
2018
Chemical informatics
ISSN 2470-6973 Vol. 4 No. 1:1
Database preparation
From the broad range of data from the scientific literature,
including biological activities for drug-like bioactive compounds as
available in the public database ChEMBL [25], information about
chemical structures, identifiers, assays and targets is extracted
and saved into the appropriate file formats for the similarity
searches in step 2. (The data in this work were based on ChEMBL
version 14 (release from July 2012) comprising almost 14 million
experimental results for about 1.9 million compounds, whereas
the current release 23 from May 2017 contains around 2.1
million compounds). The database structure of ChEMBL consists
of about 50 tables, which are mapped by primary keys and
contain information about compound, source, drug properties,
experimental data, target, mechanism of binding, etc. In order to
access the most important entity types from the database, SQL
queries were constructed and implemented in Pipeline Pilot to
extract the data about compounds, targets, assays and activities,
as well as adjustable filters for parameters like organism, activity
type, activity threshold and confidence score.
Further investigation of the ChEMBL database revealed that there
are more than 3000 different activity types measured in hundreds
of different units. Among them the top-represented activity types,
which were used in our study, are potency, EC50, IC50, inhibition,
Ki. Moreover, grouping of compounds by organisms revealed
1621 species on which they were tested. Thus, we implemented
a number of default filters for the most represented activity types
(IC50, EC50, Ki, Kd), units (M, nM, µM, mM) and organisms (human,
mouse and rat) as well as for the activity threshold (10 µM). Those
filters can be easily set via Pipeline Pilot protocol checkboxes and
variables.
To ensure as much as possible that targets are assigned to correct
assays, only records with ChEMBL confidence score higher than
7 were selected. The confidence score is assigned during the
manual curation process by the data extractors and reflects
assay-target relationships. It ranges from 0 to 9, where 0 means
uncurated data and 9 equals to high degree of confidence.
The application of above-mentioned filters reduced the amount
of ChEMBL entries from 12.3 to 3.8 million, which represents
764,419 unique registered molecules. The compounds and the
information about targets and assays were saved into separate
files. Thus, all additional information was joined to compounds
after the similarity search. We apply a predefined hierarchical
file structure for the purposes of documentation and to facilitate
further re-analyses and follow-up studies. Finally, the extracted
ChEMBL data were converted into the appropriate structure
formats required for the chosen similarity methods as described
in the next step.
Similarity search
For each compound of a combinatorial library ligand-based virtual
screens against database compounds are performed. Multiple
methodologies are applied to make maximum use of different
similarity measures. Final hit lists are combined by MAX-rank voting
as described by Baber et al. [26] and Whittle et al. [27].
In this work we implemented three approaches, namely (i) atom-
3

based circular fingerprints ECFP4, (ii) non-linear Feature Tree
descriptor FTrees and (iii) DBTOP topomer search similarities.
Each of them represents structural and pharmacophoric features
in a different and complementary way.
The extended connectivity fingerprints ECFP4 describe the
presence or absence of overlapping particular substructures [28].
The number 4 in the name corresponds to the effective diameter
of the largest feature, thus the largest possible fragment has a
width of 4 bonds. The Tanimoto coefficient is used as distance
metric for scoring.
DBTOP from Certara is a 3D similarity search where molecular
structures are compared as sets of fragments (so-called
topomers), which are characterized by CoMFA-like steric shape
and pharmacophoric features [29]. One single rule-based
conformation is generated for each fragment and oriented by
open valence bond, while the rest is oriented again using a rule-
based scheme. Aligned fragments are then compared by their
fields until the minimum topomeric difference between two
molecules is identified.
The BioSolveIT FTrees method calculates the feature tree
descriptor, which represents hydrophobic fragments and
functional groups of the molecule and the way these groups are
linked together [30]. The descriptors of two molecules are then
compared to each other.
ECFP4 and FTrees are available as Pipeline Pilot components,
whereas DBTOP was run from the command line using Pipeline
Pilot “Run on Server” component. Since we aim for target fishing
and idea generation, we accept low overall ligand similarities and
therefore limit hit lists of the individual searches by the maximum
numbers of hits and not by similarity thresholds.
The implemented Pipeline Pilot protocol allows a user to select
similarity search methods via checkboxes and to set individual
parameters for similarity threshold or number of top-hits to
save. It automatically combines results of similarity searches and
reports hits, their similarity scores as well as targets, activity and
assay data.
Analysis and selection
Hits are grouped based on the targets against which they show
activity. The results are presented as Pipeline Pilot HTML report
comprised of an interactive bar chart, representing top targets
and numbers of hits per target (Figure 2a).
The ranking order implemented here is disputable, since currently
targets are sorted by number of hits identified, which yields a
certain bias towards targets with higher numbers of congeneric
compounds reported. Since the rank score bears a certain risk
of missing interesting targets with small hit clusters, the user is
able to set a threshold for the number of targets retrieved. Up
to now, for each input library we were able to identify a set of
interesting targets. Nevertheless, alternate scoring schemes
taking into account, for instance, overall numbers of compounds
tested, activity ranges, and numbers of congeneric series will be
evaluated.
For convenient overview the bar chart is equipped with tooltips
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ISSN 2470-6973 Vol. 4 No. 1:1
and hyperlinks, showing the full target name and hit counts for
the different similarity measures. Since we are solely interested
in targets with crystal structures, information about protein
structure availability is also retrieved from RCSB Protein Data
Bank [22] and summarized in the table next to the bar chart, see
Figure 2a.
Furthermore, a click on any bar of the chart executes a Pipeline
Pilot sub-protocol, which provides a second HTML report (Figure
2b) containing table and attached structure grid view with
detailed information about the hits, e.g., chemical structure,
activity data, assay results or species on which they were tested.
Moreover, the table area and the grid view are cross-linked and
possess tooltips containing chemical structure and detailed assay
information. This gives the user a quick overview of a certain
target and its compounds as well as assists with further target
selection. The desired targets can be preselected for docking in
the next step using checkboxes.
Docking
Automated docking of library compounds, ChEMBL hits and
cocrystallized ligand into the selected targets is performed. All
available PDB structures for user-selected targets are downloaded
by the workflow, i.e., often multiple crystal structures per target.
For instance, the amount of structures deposited in PDB for cyclin-
dependent kinase 2 is more than 300. This poses a question how
to prioritize the crystal structures for docking in an automated
way. One quality criterion for a crystal structure, which can be
easily accessed, is its resolution. On the other hand, docking
may be still not successful, when it is done into a wrong protein
conformation. Since residues of apo-structure (without bound
ligand) may occupy parts of the binding pocket, we decided to
limit our docking to holo-structures (ligand-bound). Furthermore,
the presence of a ligand simplifies automated grid generation.
Thus, top N holo-structures with the best resolution are selected
for each target, where N is a number specified by the user. In
case of multiple chains, always chain A is saved for each structure
in order to simplify structural alignment. Alternative selection
schemes could include target selection by ligand similarity or
pocket shape diversity.
Ligand preparation was done in two steps. First, protonation
states at pH 7.4 for co-crystallized ligand, ChEMBL hits and library
compounds were calculated using the pKa module co-developed
by Bayer and SimulationPlus [31] and implemented as Pipeline
Pilot component “ADMET predictor” [32], while ring conformers,
tautomers and stereoisomers were generated using Schrödinger
LigPrep utility, release 9.8.
An automatic docking procedure was applied using the
Schrödinger script XGlide.py (version 3.7; v45017). The script
performs automatic protein alignment and preparation, grid
generation, re-docking of crystal structure ligands as well as
docking of other compounds (here, library compounds and
ChEMBL hits). For each selected target a separate directory
is created containing subdirectories for crystal structures,
prepared ligands and docking results. The script is executed
from the command line using Pipeline Pilot component “Run on
Server”. The following docking parameters were applied: protein
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ISSN 2470-6973 Vol. 4 No. 1:1

b)

Figure 2 The example of Pipeline Pilot protocol results: a) HTML report with cross-linked bar chart and 20 top-ranked targets derived from the
combination of three similarity search methods (DBTOP, ECFP4 and FTrees) using the designed oxadiazoles library as a starting point,
see Results Section for more details; b) example of an HTML report with cross-linked table and grid view of the hits for one specific
target, here for HTH-type transcriptional regulator EthR.

alignment, preparation and grid generation were turned on;
ligand preparation was set to false, Glide standard precision (SP)
was selected as the scoring function. The results for each target
were saved as pose viewer files, which at the end are copied into
one folder for the analysis.
Inspection
The final step in the process is by intention not automatic, and
probably can never be. The computational chemist loads docking
poses for targets of interest for visualization and analysis. In the
first step he inspects the quality of re-docking of co-crystallized
ligands and identifies commonalities and differences in the
binding modes to individual crystal structures of each target. In
the second step, he inspects docking of ChEMBL hits to verify the
interaction hot spots. Third, he analyzes the library compounds
with good and bad docking scores and judges the plausibility
of the binding modes obtained. Finally, he will either consider
biological testing of library compounds on targets of interest,
or modifying the library proposals in order to optimize their
interactions to a certain target, or generation of a completely
new library proposal.

© Under License of Creative Commons Attribution 3.0 License 5


Results
Validation of similarity search process
Of the three purely automated technical steps, namely database
preparation, similarity search and docking including grid
preparation, the most critical one for the overall performance
is the identification of targets via the similarity searches. We
therefore preformed a retrospective study in ChEMBL to test for
the performance of finding targets via searches with libraries
known to be active on those targets.
For this, we extracted ChEMBL data for compounds tested on
all species with reported IC50, EC50, Ki, Kd and activity units of
nM or µM. No activity threshold filter was set. The applied
filters reduced the number of ChEMBL entries to 851,915 which
constitute 327,520 unique molecules and 17568 different DOC_
IDs [Fussnote einfügen: DOC_ID, TARGET_ID, MOLECULE_ID all
have the same identifier name CHEMBL_ID in different tables of
the ChEML database]. From those, 633 sets based on identical
DOC_ID were derived containing between 100 and 150 molecules
each, representing our chemical libraries. This is justified by the
fact that compounds from one publication normally more or less
represents a congeneric series. The 633 sets are connected to
264 different TARGET_IDs. We finally selected 22 DOC_ID sets
which share their TARGET ID with 5 to 7 other documents (the
distribution runs between 1 and 13 different documents per
TARGET_ID).
This setup allows us to perform - using the compounds from one
document - a “library-based” similarity search. By those similarity
searches we should then be able to re-find the target the search
library is known to be active on, only based on similarity of the
library compounds to the compounds in other documents on the
target.
Detailed results are provided in Table S1 in ESI. The median
numbers of documents identified are 45 for the combined search
and 10, 43, and 7 for ECFP-4, DBTOP and Ftrees, respectively.1
We are thus always able to identify the targets of the library
compounds even though the median similarities to the ChEMBL
compounds are as expected quite low with 0.33 for ECFP-4, 139
for DBTOP and 0.88 for Ftrees. With two exceptions all targets
were identified by all three methods. Tyrosine-protein_kinase_
SYK (CHEMBL2599) was not found by ECFP-4 and Ftrees and
Cytochrome_P450_2D6 (CHEMBL289) by ECFP-4.
Thus, we are consistently able to identify the target we were
looking for, but not always at rank 1. Nevertheless, mean ranks
of the test targets are 3.5 for ECFP-4, 8.7 for DBTOP, 5.8 for Ftrees
and 1.4 for the consensus rank, which always ranks the search
target rank 1 or 2.
The hit rate and especially the ranking of the search targets is
even better than the expected outcome, i.e., that the similarity
1
During the step-wise preparation of the library sets only representative
subsets were kept via first occurance filters. This resulted in data
reduction and therefore the final numbers of DOC-IDs per target were
always lower than the numbers in the unfiltered dataset. These results
in higher numbers of documents retrieved.
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searches are performed to identify a shortlist of targets for
selection by the expert, not to identify the rank 1 targets.
Process application examples
The process described in Methods and Process Description was
developed to identify potential targets for existing chemistry-
driven combinatorial library proposals and to modify the proposals
in a way that they can directly contribute to early projects at Bayer
Pharmaceuticals Global Drug Discovery. The process is applied to
in-house libraries that are proprietary and cannot be disclosed
here. Therefore, we had to design a proof of concept case study
for this publication. The downside of this approach is that we are
not able to present experimental data for our prospective library
proposals (the starting library or the derivatives for the targets we
hit). As a starting point we chose a publication from the Journal
of Medicinal Chemistry from 2012 which describes structure-
based drug design for a series of potent 1,2,4-oxadiazoles, which
target M. tuberculosis transcriptional repressor EthR (see Figure
3a for examples) [33]. We designed a combinatorial library, that
is similar but distinct to the published compounds from ChEMBL,
with the aim to demonstrate that the developed methodology
is able (i) to recover the compounds from the publication and to
show that EthR protein can be identified among the top targets,
(ii) to identify potential new targets for our example library, (iii)
to provide examples of target-fishing-based library modifications
and (iv) to provide examples of the short-comings of such a fully
automatic approach and to highlight the importance of expert
interaction.
In particular, we introduced three changes to our library with
respect to the library from the publication. First, we modified the
piperidine ring to a cyclo-hexyl, i.e., shifted the nitrogen by one
position. Second, we replaced the aliphatic lipophilic side chain
by various R2 groups of different size, polarity and charge state,
connected via nitrogen or amide bonds. Third, we introduced
alternative lipophilic R1 groups at the only point of variation
from the published library. Core definitions and examples for the
publication and the library compounds are shown in Figures 3a
and 3b, respectively.
Example of database preparation: Step 1 of the workflow is to
search for similar compounds and their associated targets using
the designed library as a reference. For now, ChEMBL data were
extracted for compounds tested on all species with reported IC50,
EC50, Ki, Kd and activity units of nM or µM. No activity threshold
filter was set. The applied filters reduced the number of ChEMBL
entries to 851,915 which constitute 327,520 unique molecules.
Example of similarity search: In step 2, similarity searches are
performed. We used all three currently implemented methods,
namely DBTOP, ECFP4 and FTrees as described in Methods. 400
highest rank hits were saved for each metric, and additionally a
consensus rank was calculated. The diagram in Figure 2a gives
the list of the top 20 targets, associated with the results of the
similarity searches, as interactive bar chart. Table S1 of Supporting
Information provides more detailed information about target
ranks according to the three similarity search methods and
consensus rank; additionally, it lists the numbers of identified
hits and PDB structures for each target. The targets in Table S1

Figure 3 Schematic representation of cores and example compounds for: a) M. tuberculosis transcriptional repressor EthR inhibitor series
from the publication of Flipo et al. [28]; b) combinatorial oxadiazole library.
are sorted by descending number of ligands identified by ECFP4
similarity search. As mentioned earlier, the implemented ranking
by number of hits per target may be biased towards the targets
with large congeneric series.
Example of analysis: Step 3 is the first of two expert intervention
steps. Target selection could be done automatically based on
their ranks, but manual selection will allow to concentrate on
targets relevant in the context of a company’s research portfolio.
The transcriptional repressor EthR was ranked number 7 by
the consensus score, which combines the results of the three
similarity search methods. The scoring according to ECFP4 method
ranked EthR on position three. ECFP4 was able to identify all 33
© Under License of Creative Commons Attribution 3.0 License
2018
Chemical informatics
ISSN 2470-6973 Vol. 4 No. 1:1
compounds from the publication, whereas FTrees found only 2
and DBTOP none, underlining the necessity to apply multiple
ligand-based search methods to obtain the complete picture.
DBTOP is based on steric and pharmacophoric fields of the
whole molecule and therefore is more susceptible to larger size
differences between query and database molecules than FTrees,
which abstracts the molecular fragments into pharmacophoric
representations, or ECFP4 circular fingerprints, where the hits
are dominated by occurrences of fragment features. Depending
on library, contributions of different methods will differ. Some in-
house library screens, for instance, were dominated by DBTOP
hits. It is a priori not obvious which similarity metric will dominate
in the consensus hit list.
7

Figure 4 shows the example hits identified by different similarity
search methods to underline this assumption. It is worth to note
that similarity scores (see Table S2 of Supporting Information) as
expected are quite low, pointing out that chemical modification
of the library compounds guided by the final docking step might
be needed.
As expected, the numbers of hits for the different search methods
differ. But in addition, also the numbers of PDB structures retrieved
differ. For instance, 33 PDB structures of 11-beta-hydroxysteroid
dehydrogenase 1 are found using only ECFP4 (see Table S1),
whereas the combination of three similarity methods retrieved
38 PDB entries. The reason for this lies in the fact that all ECFP4
hits are annotated with UniProt [34] identifier P28845 (human)
whereas the combination of ECFP4 and FTrees resulted in hits,
which were tested on human and mouse 11-beta-hydroxysteroid
dehydrogenase 1 (UniProt identifiers P28845 and P50172,
respectively). While the human sequence shares 79% identity
to the mouse orthologue, there is high level of conservation of
amino acids in the binding site. All ECFP4 hits share the same
oxadiazole motif while FTrees identified two additional motifs
(Figure 5). Again, it is strongly emphasized that it is advantageous
to employ multiple ligand similarity metrics.
Our proof-of-concept target EthR is rank seven by consensus
score and rank three by ECFP4 similarity search. In the following
we will analyze the two top-ranked targets in more detail (see
also Table S1), together with our target of interest, EthR (which
would resemble the real-life situation with some targets in the
list not being relevant for the current portfolio.
Example of docking: For step four we selected the two
top-ranked targets for docking, namely, top-ranked target
metabotropic glutamate receptor 5, second-ranked receptor
smoothened homolog, and our proof-of-concept target HTH-
type transcriptional regulator EthR which is ranked seventh.
The docking of our library compounds, ChEMBL hits and co-
crystallized ligands was performed using the fully automated
XGlide procedure as described in Methods. A maximum of 2
crystal structures per target were retrieved automatically. We
had to extend the set by one more structure in the case of EthR,
as described in the following.
Our decision objective for target fit is correct re-docking of the
co-crystallized ligand, consistent docking of the ChEMBL hits and
Figure 4 An example of two ChEMBL hits obtained by similarity search for the designed oxadiazole library using different similarity methods -
compound 7 (inhibitor of anandamide aminohydrolase) was identified by DBTOP similarity and compound 8 (inhibitor of cytochrome
P450) by FTrees and ECFP4.
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finally consistent docking of the library compounds or similarly
decorated subsets thereof. We provide docking scores as a means
of further confirmation of consistent placement, but not as a filter
or design criterion per se. High docking scores are a strong hint
for important interactions to the target matched, whereas low
scores are not always correlated to weak binding interactions.
Helix-Turn-Helix-type (HTH-type) transcriptional
regulator EthR
Currently there are 23 protein structure entries in RSCB protein
data bank based on UniProt ID accession code P9WMC1
(Mycobacterium tuberculosis). Since the number of structures for
docking is actually a compromise between expected information
gain and effort, two structures for docking were automatically
selected from the 17 holo-structures available, based on crystal
structure resolution. By default, we process two different crystal
structures since modelling experience tells that using multiple
target structures for rigid docking reduces the risk of missing
important target information. We later added one additional
structure, namely 3O8H, due to its different pocket shape and
ligand-binding mode.
The hits found by ECFP4 are both agonists and antagonists with
best EC50 of 60 nM and IC50 of 400 nM, respectively, i.e., highly
active compounds.
G1M: An example where library fits well into the target: Docking
of the library compounds into the first crystal structure 3G1M
with a resolution of 1.7 Å yields in high docking scores and
poses comparable to the co-crystallized ligand (IC50 of 500 nM,
retrieved from PDB Bind [35]). An additional hydrogen bond
to Asn176 can be observed between EthR and some of library
compounds containing tertiary amine or amide linker attached
to the oxadiazole-cyclohexane core (an example can be seen
in Figure 6). In contrast, the co-crystallized ligand, which has
an oxadiazole-piperidine scaffold, is missing a hydrogen bond
donor at this position. Moreover, the analysis of the binding
pocket around the ligand can provide further suggestions for
compound modifications, e.g., for extended interactions into the
hydrophobic pocket formed by Met102, Val152, Leu90.
3Q0W: differences in protein conformation and incomplete
binding site setup: In contrast, docking into the second EthR
structure (co-crystallized ligand has Ki of 400nM [35]) led to

Figure 5 Exemplary ECFP4 hit 9 for human target 11-beta-hydroxysteroid dehydrogenase 1 and structurally different FTrees hits 10 and 11 for
mouse protein.
Figure 6 HTH-type transcriptional regulator EthR (3G1M, light grey representation) with co-crystallized ligand (cyan) and docking solution for
one library compound (magenta, glide SP score=-12.40).
low-scored poses for our library compounds. It turned out that
a cocrystallized glycerol molecule, that had not been removed
by the automated protein preparation, was situated deep in the
binding site, establishing hydrogen bond to Asn176 and blocking
ligand entry.
After its removal, docking of all compounds was possible.
Nevertheless, the poses are still quite inconsistent. The amide
moiety for about half of the poses is located deep in the pocket
and makes hydrogen bonds to Asn176 and Asn179, analogously
to the 3G1M dockings shown in Figure 6, and for the other half
it points out of the pocket. Such differences can be explained
by conformational flexibility of the protein, which can be seen
© Under License of Creative Commons Attribution 3.0 License
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in comparison of the two EthR crystal structures (PDB codes
3G1M and 3Q0W, the superimposition is shown in Figure S1, see
Supporting Information). Slight but pronounced differences can
be observed at the loop region (residues Asn93-Asp98), where
the flip of Pro94 is accompanied by narrowing the entry channel,
which sterically hinders the placement of substituents towards
this loop in 3G1M.
3O8H: Alternate binding mode: Our library was intentionally
designed to be chemically similar to the EthR inhibitor BDM41906
[33] (PDB ID: 3SFI). 3G1M and 3SFI have the same overall shape,
the library compounds dock consistently into both pockets
(results are not shown).
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Nevertheless, closer inspection of EthR structures revealed a
second set of crystal structures with considerably larger binding
pocket. Such pocket enlargement is mainly caused by the flip of
side chains of Thr121, Gln125, Trp138 and Phe184 (see Table S3
for comparison of available EthR crystal structures).
Figure 7a shows the alignment of 3G1M and 3O8H along with
interaction volumes generated by SiteMap [36]. As expected,
cross-docking of the 3O8H ligand (IC50=580 nM) into the rigid
3G1M receptor, without taking into account any induced fit
effect, yields a completely different and wrong binding mode,
where the aromatic sulfonamide is pointing out of the pocket
(see Figure 7b).
About two thirds of the library members dock consistently to
BDM41906. About one third, due to the pronounced pocket
differences, dock inconsistently. Library members from both sets
ignore the additional cavity available in 3O8H.
In summary, we were in fact able to identify EthR as a potentially
interesting target based on ligand similarity and docking results
for our designed oxadiazole library. We have also demonstrated,
that further optimization strategy largely depends on the choice
of EthR crystal structure, since the pocket residues are the subject
of conformational changes. Based on the docking results from
both pocket shapes, we gained worthwhile additional information
about flexible and rigid subpockets and key interaction features.
If it were for our library extension campaign, we would now,
based on the target information, slightly optimize the decoration
of the initial library and additionally design a second library that
targets the deep cavity available in 3O8H. We would cross-check
the design for IP space and if necessary iteratively adjust to create
novelty.
Metabotropic glutamate receptor 5
The highest ranked target according to ECFP4, the metabotropic
glutamate receptor 5, is a class C G-protein-coupled receptor
responding to the neurotransmitter glutamate. There is only
one holo structure (PDB ID 4OO9) identified in PDB for the
transmembrane ligand-binding domain, since earlier structural

a)

ab)

Figure 7 a) Alignment of crystal structures 3G1M (green residues) and 3O8H (cyan residues), protein ribbons are depicted in light grey. Amino
acids with different side chain orientations responsible for change in pocket shape are shown as sticks. SiteMap [31] generated
surfaces are shown in blue mesh for 3G1M and magenta mesh for 3O8H; b) Overlay of the crystallized 3G1M ligand (green), the
crystallized_3O8H ligand (cyan) and the docking pose of the 3O8H ligand in 3G1M (magenta).

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studies had been restricted to the amino-terminal extracellular
domain, providing little understanding of the membrane-
spanning signal transduction domain. 4OO9 is co-crystallized in
complex with the negative allosteric modulator, mavoglurant.
The similarity searches for the library compounds identified
in total 160 agonists and antagonists of the metabotropic
glutamate receptor 5 using consensus scoring, with best affinity
values of EC50=5 nM, IC50=130 nM, and Ki=150 nM. The ECFP4
method ranked this target at the top position, while FTrees
ranked it at the position three with 149 and 25 inhibitors being
identified, respectively. There were no metabotropic glutamate
receptor 5 inhibitors among top 25 targets identified by DBTOP
method. The hits represent different structural clusters such as
piperidine-amides, piperidine-sulfonamides and spiro-hexyl-4,5-
dihydrooxazoles (see Figure 8 for examples).
4OO9: Failure of the automatic procedure: All steps of the
automatic workflow technically proceeded well and compounds
were successfully docked. However, a closer look at the crystal
structure 4OO9 revealed that during automated protein
preparation and docking, the docking grid was positioned
around a co-crystallized small organic molecule coming from the
experimental conditions, namely oleic acid, and not around the
allosteric modulator mavoglurant [37]. Thus, the docking was
performed into the wrong pocket (see Figure S2 of Supporting
Information).

Figure 8 Representative hits for metabotropic glutamate receptor 5.

Figure 9 Example docking solution of library compound (magenta ligand) using manual grid set up (glideSP=-10.33) into metabotropic
glutamate receptor 5 structure 4OO9 (protein is shown as light grey cartoon). The crystal structure ligand is shown as cyan sticks.

© Under License of Creative Commons Attribution 3.0 License 11


The example of 4OO9 shows that the fully automated docking
procedure has its drawbacks. Protein preparation and docking
setup require user inspection and in certain cases manual
correction. The effort nevertheless is acceptable, since the expert
should be knowledgeable of the target in order to understand
and to judge the observed ligand interactions. On the other hand,
one could implement a mechanism to retrieve information about
the actual ligand and its binding mode, and use it during the
protein preparation step.
Docking into the manually prepared binding site reveals that our
library compounds exhibit numerous interactions to the receptor
similar to the crystal structure ligand, e.g., hydrogen bonds to Asn-
747 and Ser-809, and extend their interactions deeper into the
pocket lined out by Arg-648 and Val-740 (see Figure 9), which can
be further analyzed to guide possible compound modifications.
Smoothened homolog
The Smoothened (SMO) receptor is a key signal transducer in the
Hedgehog (Hh) signalling pathway. SMO is classified as a class
F (frizzled) G-protein-coupled receptor (GPCR). It contains the
conserved seven-transmembrane helical fold common to the
class A GPCRs and an unusually complex arrangement of long
extracellular loops stabilized by four disulphide bonds.
The similarity search for the library compounds identified overall
111 SMO inhibitors with a best IC50 of 16 nM, using consensus
scoring. 103 hits arose from ECFP4 search and 20 hits from
FTrees. All hits are piperidine-amides or piperidine-ureas, but
again FTrees was able to detect more diverse compounds.
4JKV: Optimizing the library for the target: The 2.5 Å resolution
crystal structure of the human SMO receptor contains the
Figure 10 SMO inhibitor crystal structure ligand LY2940680 15 (PDB code: 4JKV), two representative library compounds 16 and 17 and the
modified hybrid compound 18.
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transmembrane domain together with antagonist LY2940680 15
(see Figures 10 and 11), which binds the extracellular end of the
seven-transmembrane-helix bundle via extensive contacts to the
loops. Redocking reproduced the binding mode with an RMSD of
0.52 Å.
Docking into Smoothened homolog resulted in many well-scored
solutions for the ChEMBL hits and library compounds with
consistent docking poses (see Figure 11 for examples).
Instead of the conserved hydrogen bond between the carbonyl
group of ligand and Asn219, which is observed for most of the
ChEMBL inhibitors and LY2940680, the library compounds form
one or two (e.g., ligands with positively charged aliphatic ring like
compound 16, see Figures 10 and 11) additional hydrogen bonds
with the backbone carbonyl of Tyr394.
On the downside, most of the library compounds do not pi-stack
to Phe484. Exceptions are, for instance, sulfonamides like 17 (see
Figure 11). One of oxadiazole nitrogens of library compounds
usually participates in hydrogen bonding to Arg400 analogous to
the phtalazine nitrogens in the crystal structure [38], but none
of the library compounds is able to fill the hydrophobic pocket
occupied by the phtalazine core.
The observations about key interactions of LY2940680 15 and
the ChEMBL compounds provide us ideas for possible library
modifications in order to target SMO binding pocket optimally.
Figure 11b shows an example of hybrid compound 18 which has
the oxadiazole replaced by phtalazine core while keeping the
larger p-cyanophenyl and the positively charged pyrrolidino-
amide. The Glide SP docking score for 18 (-12.39) is virtually
identical to 15 (-12.66). Alternate hetero-bicycle replacements
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a)

a)

Figure 11 Docking into the smoothened (SMO) receptor (4JKV: protein is shown as light grey cartoon). a) redocked LY2940680 15 (cyan
sticks) and docking poses of two library compounds 16 and 17 (green and magenta); b) LY2940680 15 (cyan) and the docking
pose of modified hybrid 18 (green sticks), the phtalazine cores of both compounds are well-aligned.

© Under License of Creative Commons Attribution 3.0 License 13


also fit well. Aromatic headgroups linked via sulfonamide or amide
like in compound 17 (glideSP=-11.47), on the other hand, are able
to participate in pi-stacking with Phe484. Overall, from the point
of view of target interactions, there is a bunch of options, with
similar but also better Lipinski properties than LY2940680 having
a molecular weight of 512 Da and an AlogP of 4.56.
Conclusion
When planning for the extension of a compound library, one
is confronted with a universe of synthesis options. The only
limitations, thus, are one’s own creativity, lab and budget
resources in order to transform the ideas into chemical libraries.
Therefore, a rational concept to explore the options and pick
the libraries with a certain probability to hit biological targets is
desirable. Expert knowledge can guide the planning procedure.
However, in such case the library design can be limited to the
person’s experience around the projects he has worked on.
Metrics like ligand efficiency allow to stay in an attractive property
profile range but do not assist the selection of compounds
amenable to target families of interest. Although drug-likeness or
target class-likeness scores take into account overall similarity to
known drugs or actives, substructure or global pharmacophore
features are quite rough estimates of target family fit.
In this paper we therefore describe the productive implementation
of a concept aiming, on one hand, to identify putative targets for
a chemistry-driven library proposal and, on the other hand, to
identify options for compound modifications in order to create
new libraries better fitting to certain targets. This article reports
on a designed virtual combinatorial library and hits identified by
the workflow, as well as on library modification ideas without the
desirable proof of synthesis and experimental testing.
The real in-house examples cannot be disclosed here, and
the examples shown will not trigger any synthesis and testing
at Bayer. Currently we are still not able to provide significant
statistics about success rates of the described workflow due to its
novelty and the long turn-around times for the process of library
design, out-sourced chemical realization, registration and testing.
Our workflow aims to automate all tedious time-consuming
technical steps and allow to concentrate on rational design. We
always start with a chemistry-driven library carefully checked
for novelty and end up with a proposal that again is checked for
novelty as a part of the design procedure.
The workflow is divided into a set of protocols implemented in
Pipeline Pilot that control the crucial steps, run automatically
and require minimum user interaction which is productively
used at Bayer Drug Discovery. The implementation described
in this paper compares a virtual compound library to the
chemical space represented in ChEMBL by multiple ligand-based
similarity metrics, retrieves ligand and target information and
presents the results in an intuitive representation to an expert,
who then decides whether to proceed with ligand design for
targets of interest. The protocol automatically retrieves PDB
structures and sets up docking runs for the cocrystallized ligand,
the ChEMBL compounds and library structures. The most time-
consuming step is, by design, the final one, i.e., the visual
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inspection by a computational chemist, who can further trigger
library modifications or re-design. The system is easy to use and
it is highly productive. The workflow is modular and can easily
be extended to alternate database sources, similarity metrics,
hit prioritization algorithms, or docking protocols. Due to its
accessibility, the ChEMBL database was chosen as a source of
biological and chemical information. However, incorporation of
alternate data sources is obvious.
As expected, the first part of the process, which is strictly ligand-
based, is highly reliable and fast. The use of multiple similarity
metrics is advantageous since various approaches represent
chemical similarity differently, and the consensus-based
assessment serves as a good basis for more detailed analysis of
hits and their corresponding targets and for inspiring creativity
in library design. The platform is open for the incorporation
of alternate methods, e.g., shape-based screening or
pharmacophore fingerprints. The current target ranking, which
is based on the number of hits identified, is not optimal, since it
favors large congeneric series. Thus, further modifications to the
protocols are ongoing work.
It stands to reason that common challenges of structure-based
drug design are especially relevant for an automated procedure,
and special attention should be given to it. One of issues
concerns the assignment of ligand protonation states, which
nevertheless can be reliably estimated by modern pKa predictor
software. Correct stereochemistry is more problematic. There
are cases where stereochemistry of a PDB ligand is ambiguous;
stereochemistry of ChEMBL compounds is not always explicitly
defined, and library compounds may exist as racemates or with
unknown configuration depending on a synthesis route. The
best compromise here is to enumerate relevant stereoisomers
and to let the binding pocket decide. Finally, we are faced with
incorrect bond orders in a PDB ligand and unknown tautomer
forms of ChEMBL or library compounds. Tautomerism is an issue
still lacking a sound solution. It is dealt by rule-based generation
and docking of sets of tautomers.
Another issue concerns the protein preparation step. As we
have shown in this paper, automatic preparation will sometimes
detect a wrong binding site or not remove small co-crystallized
substances. In the current XGlide implementation, all crystal
waters are removed. Therefore, a fraction of automatically created
results has to be discarded and manually re-processed. Even if
there is still room for improvement, we consider that currently
XGlide is one of the best solutions for automatic preparation,
protein alignment and docking.
The third step of docking and scoring also has its limitations which
are well described in the literature. A consistent binding mode of
library compounds is a necessary but not sufficient condition for
a compound binding to a target, especially since docking scores
are often misleading. These issues together with limitations of
previous steps, e.g., complete removal of waters that sometimes
provide important contacts to a target, are the main pitfalls of the
automatic procedure. Thus, close visual inspection by an expert,
who is knowledgeable of a target, will finally allow to judge the
relevance of results.
This article is available in: http://cheminformatics.imedpub.com/

One could argue whether it is worth to use an automatic process
with its numerous limitations. In our opinion, the advantages by
far outweigh the risks. The process allows an expert to set up a
query very easily and to put his time on analysis and re-design
of the library. Walking through a full process takes about ten
to thirty minutes for a set-up, about 4-8 h for data extraction
and similarity search, and about 2 to 3 h for docking per crystal
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